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In 2022, the American Cancer Society estimates that over 34,000 men will die of PCa, largely due to metastatic PCa. Up to 90% of advanced prostate cancers metastasize to bone, and there are currently no curative therapies for bone metastatic prostate cancer (BM-PCa). BM-PCa cells interact with bone-forming osteoblasts and bone-resorbing osteoclasts to induce aberrant bone remodeling, which leads to skeletal related adverse events such as increased risk of fractures, bone pain, and poor quality of life. Mesenchymal stem cells (MSCs) are multipotent stem cells that can differentiate into osteoblasts. Cook lab data show BM-PCa cells interact with MSCs and promote MSC differentiation into osteoblasts. Microarray analysis of MSC gene expression changes in response to BM-PCa show significant upregulation of CXCL8. To determine the importance of MSC-derived CXCL8 to BM-PCa, CXCL1 (the murine homolog of CXCL8) was genetically deleted in murine MSCs. While CXCL1 knock out (KO) had no significant impact on MSC proliferation, loss of CXCL1 decreased MSC migration, which suggests upregulation of MSC CXCL1 by BM-PCa cells functions to increase MSC migration into the tumor microenvironment. Additionally, CXCL1 KO MSCs have altered osteoblastic differentiation, whereas adipogenic differentiation was unchanged. RNA sequencing of MSCs stably expressing CXCL1-targeted shRNAs compared to scrambled controls show extensive gene expression changes, including altered expression of multiple osteogenic genes. In vivo data show intratibial co-injection of CXCL1 KO MSCs with murine RM1 BM-PCa cells in an immunocompetent mouse model increases tumor burden compared with co-injection of wildtype MSCs and BM-PCa cells, indicating a role for MSC-derived CXCL1 in suppressing BM-PCa tumor growth in bone. This project shows for the first time the importance of CXCL1 in MSC migration, osteogenesis, gene expression, suppression of BM-PCa progression in bone and tumor-induced bone remodeling. Citation Format: Catherine S. Johnson, Diane Costanzo-Garvey, Massar Alsamraae, Jeremy S. Frieling, Leah M. Cook. Role of MSC-derived CXCL1 in bone-metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 82. |
